Indole and 2,3-dihydroindole derivatives, their preparation and use

ABSTRACT

The present invention relates to indole and 2,3-dihydroindole derivatives having formula (I)                    
     or any of its any of its enantiometers or any mixture thereof, or an acid addition salt thereof, wherein A, R 1 , R 2 , R 3 , W, X, Y and Z are as described in the description. The compounds are potent serotonin reuptake inhibitors and have 5-HT 1A  receptor antagonistic activity.

This is a division, of application Ser. No. 09/491,204, filed Jan. 25,2000 now U.S. Pat. No. 6,476,035 which is a continuation ofInternational application no. PCT/DK98/00336, filed Jul. 20, 1998, whichclaims benefit under 35 U.S.C. §119(e) of U.S. provisional applicationNo. 60/053,713, filed Jul. 25, 1997. Each of these prior applications ishereby incorporated herein by reference, in its entirety.

The present invention relates to novel indole and 2,3-dihydroindolederivatives which are potent serotonin reuptake inhibitors,pharmaceutical compositions containing these compounds and the usethereof for the treatment of disorders or diseases responsive to theinhibition of serotonin re-uptake. The compounds of the invention alsopossess antagonistic activity at 5-HT_(1A) receptors and are consideredto be particularly useful for the treatment of depression.

BACKGROUND

Selective serotonin (or 5-HT) reuptake inhibitors (SSRI's) such asfluoxetine, paroxetine, sertraline, fluvoxamine and citalopram representa major step forward in the treatment of depression because they havefewer and less severe side effects compared to first generationantidepressant (tricyclics and non-selective MAO inhibitors). The sideeffects associated with first generation antidepressants are such thatthey cause some patients to withdraw from treatment.

SSRI's and all other antidepressants currently available suffer from aserious drawback in that several weeks of treatment is necessary toproduce the therapeutic effect. The late onset of action is asignificant problem, particularly in the treatment of patients withsevere depression and suicide potential. Further, one in three patientsare not responsive to SSRI's.

Electrophysiological experiments in rats have shown that acuteadministration of SSRIs reduces firing of 5-HT neurons of dorsal raphenucleus in the rodent brain, whereas sustained treatment with SSRIsleads to normalization of the firing activity of the 5-HT neurons(Arborelius, L. et al, Naunyn-Schmiedeberg's Arch. Pharmacol. 1995, 352,157; Gartside, S. E. et al, Br. J. Pharmacol. 1995, 115, 1064; Chaput,Y. et al, Naunyn-Schmiedeberg's Arch. Pharmacol. 1986, 33, 342).

Further, it has been shown that the recovery of the firing activity of5-HT neurons is linked to desensitization of somatodendritic 5-HT_(1A)autoreceptors (Le Poul, E. et al, Naunyn-Schmiedeberg's Arch. Pharmacol.1995, 352, 141; Invernizzi, RE. et al, Eur. J. Pharmacol. 1994, 260,243).

It has thus been suggested that simultaneous administration of SSRIs andan agent causing rapid desensitization or inhibition of the 5-HT_(1A)receptor mediated feed back mechanism would lead to rapid onset ofantidepressive effect (Artigas, F. et al, Trends Neurosci. 1996, 19,378; De Vry, J., et al, Drug News Perspec. 1996, 9, 270)

The effect of combined administration of a compound that inhibitsserotonin reuptake and a 5-HT_(1A) receptor antagonist has beenevaluated in several studies (Innis, R. B. et al., Eur. J. Pharmacol.,1987, 143, p 195-204 and Gartside, S. E., Br. J. Pharmacol. 1995, 115, p1064-1070, Blier, P. et al, Trends Pharmacol. Sci. 1994, 15, 220). Inthese studies it was found that 5-HT_(1A) receptor antagonists inhibitthe decrease in firing caused by acute administration of serotoninreuptake inhibitors.

Further, treatment with a combination of pindolol (a well known5-HT_(1A) receptor and β-adrenoceptor antagonist) and SSRI's has beenevaluated in clinical trials. A remarkable improvement of the mood ofpatients was reported within one week. In addition, combinedadministration of pindolol and a SSRI was shown to have a good effect onpatients who were non-responsive to treatment with currently availableantidepressants (Artigas F. et al., Arch. Gen. Psychiatry, 1994, 51, p248-251 and Blier, P. et al., J. Clin. Psychopharmacol. 1995, 15, p217-222).

Several patent applications have been filed which cover the use of acombination of a 5-HT_(1A) antagonist and a serotonin reuptake inhibitorfor the treatment of depression (see EP-A2-687 472 and EP-A2-714 663).

In EP-A1-529 462 certain 1,4-benzodioxan derivatives having the generalformula

wherein B is an optionally substituted indol-3-yl group and Q isC_(n)H_(2n) wherein n is 1, 2, 3, 4, 5, or 6 are disclosed. Thesecompounds are said to have serotonin agonistic and serotoninantagonistic activity as well as serotonin reuptake inhibiting activityand to be useful as anxiolytics, antidepressants, antipsychotics,antihypertensives, and cerebroprotective agents.

In U.S. Pat. No. 5,200,948, Perregaard et al., disclose related indoles,indazoles, 2-indolones and 2,3-dihydro derivatives thereof having theformula

wherein X is —CH—, —CH₂—, —NH—, or —CO—; and Ar is

wherein Y is O, or S, Z is O, S, or —CH₂—, and n is 1, 2, or 3.

These compounds are valuable 5-HT_(1A) receptor ligands.

OBJECT OF THE INVENTION

It is the object of the present invention to provide compounds withpotent serotonin reuptake inhibiting activity as well as antagonisticproperties at 5-HT_(1A) receptors. Such compounds may be useful as fastonset of action medicaments for the treatment of affective disorders,such as depression.

A further object of the present invention is to provide a pharmaceuticalcomposition comprising the above compounds as active ingredients.

SUMMARY OF THE INVENTION

The invention then, inter alia, comprises the following alone or incombination:

An indole or 2,3-dihydro-indole derivative having the formula

any of its enantiomers or any mixture thereof, or an acid addition saltthereof, wherein

X is —O—, —S—, or —CR⁴R⁵—; and

Y is —CR⁶R⁷—, —CR⁶R⁷—CR⁸R⁹—, or —CR⁶═CR⁷—; or

X and Y together form a group —CR⁴═CR⁵—, or —CR⁴═CR⁵—CR⁶R⁷—;

Z is —O—, or —S—;

W is N, C, or CH;

A is a group selected from a group of formula (II), (III) and (IV)

wherein the dotted lines mean an optional bond;

R¹, R², R³, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are each independentlyselected from hydrogen, halogen, trifluoromethyl, alkyl, alkenyl,alkynyl, cycloalkyl, alkoxy, hydroxy, formyl, acyl, amino, alkylamino,dialkylamino, acylamino, alkoxycarbonylamino, aminocarbonylamino,alkylaminocarbonylamino, dialkylaminocarbonylamino, nitro, cyano, andaryl or arylalkyl wherein aryl may be substituted with halogen,trifluoromethyl, alkoxy, hydroxy, amino, alkylamino, nitro and cyano;

R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogenand alkyl; and

R¹¹ is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, acyl and formyl.

In one embodiment of the invention Z is —O—, and the other substituentsare as defined above.

In another embodiment of the invention Z is —S—and the othersubstituents are as defined above.

In a third embodiment of the invention A is a group of formula (II) andthe other substituents are as defined above.

In a fourth embodiment of the invention A is a group of formula (III)and the other substituents are as defined above.

In a fifth embodiment of the invention A is a group of formula (IV) andthe other substituents are as defined above.

Thus, in a special embodiment of the invention A is a group of formula(II) and Z is —O, A is a group of formula (III) and Z is —O—, A is agroup of formula (IV) and Z is —O—, A is a group of formula (II) and Zis —S—, A is a group of formula (III) and Z is —S—or A is a group offormula (IV) and Z is —S—.

In a further embodiment of the invention R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ areselected from hydrogen or methyl.

Examples of compounds according to the invention are

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-bromo-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-2-methyl-1H-indole,

6-Chloro-3-[2-[4-(2,2,5-trimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl]ethyl]-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-4-chloro-1H-indole,

6-Chloro-3-[2-[4-(2,2,-dimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl]ethyl]-1H-indole,

6-Chloro-3-[2-[4-(2,2,-dimethyl-2,3,-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl]-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-methoxy-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-methyl-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-methyl-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,

3-[2-[4-(5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole,

6-Chloro-3-[2-[4-(5-chloro-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole,

6-Chloro-3-[2-[4-(6-chloro-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-8-yl)piperazin-1-yl]ethyl]-1H-indole,

6-Chloro-3-[2-[4-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-4-methyl-1H-indole,

3-[2-[4-(7-Chloro-1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,

2-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,

1-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-2,3-dihydroindole,

6-Chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl]-6-chloro-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperidin-1-yl]ethyl]-6-chloro-1H-indole,

3-[2-[4-(1,4-Benzodioxin-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,

3-[2-[4-(Benzofuran-7-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole, and

3-[2-[4-(1,3-Benzodioxolan-4-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,

6-Chloro-3-[2-[4-(6-Chloro-1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole,

5-Chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole,

3-[2-[4-(2,3-Dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole,

3-[2-[4-(Benzothiophen-7-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,

3-[2-[4-(Benzothiopyran-8-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,

3-[2-[4-(Benzothiopyran-8-yl)piperazin-1-yl]ethyl]-5-bromo-1H-indole,

3-{2-[4-(Benzothiopyran-8-yl)piperazin-1-yl]ethyl}-6-chloro-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-chloro-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-fluoro-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperidin-1-yl]ethyl]-6-chloro-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperidin-1-yl]ethyl]-5-chloro-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperidin-1-yl]ethyl]-5-fluoro-1H-indole,

6-Chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-1H-indole,

3-[2-[4-(Benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-6-chloro-1H-indole,

3-[2-[4-(Benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-bromo-1H-indole,

3-[2-[4-(Benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-fluoro-1H-indole,

3-[2-[4-(Benzofuran-7-yl)piperidin-1-yl]ethyl]-6-chloro-1H-indole,

3-[2-[4-(Benzofuran-7-yl)piperidin-1-yl]ethyl]-5-fluoro-1H-indole,

3-[2-[4-(Benzofuran-7-yl)piperidin-1-yl]ethyl]-5-bromo-1H-indole,

1-Acetyl-3-[2-[4-(1,4-benzodioxan-4-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1H-indole,

1-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole,

1-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,

1-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole,

1-[2-[4-(2,3-Dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-5-fluoro-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-2,3-dihydro-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-1-butyl-1H-indole,

1-Allyl-3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-1-propargyl-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1-methyl-1H-indole,

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-1-benzyl-2,3-dihydro-1H-indole,

1-Allyl-3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1H-indole,

1-Acetyl-3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole,

3-[2-[4-(Benzo-1,4-dithian-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,

3-[2-[4-(Benzo-1,4-dithian-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,

3-[2-[4-(Benzo-1,4-dithian-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole,

3-[2-[4-(Benzo-1-thia-4-oxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,

3-[2-[4-(Benzo-1-thia-4-oxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,and

3-[2-[4-(Benzo-1-thia-4-oxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole,

or an acid addition salt thereof.

The invention also relates to a pharmaceutical composition comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand at least one pharmaceutically acceptable carrier or diluent

In a further embodiment, the invention relates to the use of a compoundof formula (I) or a pharmaceutically acceptable acid addition saltthereof for the preparation of a medicament for the treatment of adisorder or disease responsive to the inhibition of serotonin reuptakeand antagonism of 5-HT_(1A) receptors.

In particular, the invention relates to the use of a compound accordingto the invention or a pharmaceutically acceptable acid addition saltthereof for the preparation of a medicament for the treatment ofaffective disorders, such as depression, psychosis, anxiety disordersincluding general anxiety disorder, panic disorder and obsessivecompulsive disorder.

In still another embodiment, the present invention relates to a methodfor the treatment of a disorder or disease of living animal body,including a human, which is responsive to the inhibition of serotoninreuptake and antagonism of 5-HT_(1A) receptors comprising administeringto such a living animal body, including a human, a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable acid addition salt thereof.

In particular, the invention relates to a method for the treatment ofaffective disorders, such as depression, psychosis, anxiety disordersincluding general anxiety disorder, panic disorder and obsessivecompulsive disorder comprising administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptableacid addition salt thereof to a living animal body, including a human,in need thereof.

Due to their combined antagonism of 5-HT_(1A) receptors and serotoninreuptake inhibiting effect, the compounds of the invention areconsodered particularly useful as fast onset of action medicaments forthe treatment of depression. The compounds may also be useful for thetreatment of depression in patients who are resistant to treatment withcurrently available antidepressants.

The compounds claimed herein are considered particularly useful for thetreatment of depression requiring fast onset of antidepressive effect,or a depression which is resistant to other antidepressants.

Halogen means fluoro, chloro, bromo, or iodo.

Alkyl means a straight or branched chain of one to four carbon atoms,including for example, methyl, ethyl, propyl, isopropyl and butyl.

Alkenyl means a chain of from two to four carbon atoms containing onedouble bond, including for example ethenyl, 1-,2-propenyl, 2-,3-propenyletc.

Alkynyl means a chain of from two to four carbon atoms containing onetriple bond, including for example ethynyl, 1-,2-propynyl, 2-,3-propynyletc.

Cycloalkyl means cyclic alkyl of from three to seven carbon atoms,including cyclopropyl, cyclobutyl etc.

Alkoxy is —O-alkyl where alkyl is as defined above.

Acyl means —CO-alkyl wherein alkyl is as defined above.

Alkylamino means —NH-alkyl, and dialkylamino means —N—(alkyl)₂ wherealkyl is as defined above.

Acylamino means —NH-acyl wherein acyl is as defined above.

Alkoxycarbonylamino means alkyl-O—CO—NH— wherein alkyl is as definedabove.

Alkylaminocarbonylamino means alkyl-NH—CO—NH— wherein alkyl is asdefined above.

Dialkylaminocarbonylamino means (alkyl)₂—NH—CO—NH— wherein alkyl is asdefined above.

Aryl means an aromatic ring such as phenyl, or napthyl.

Arylalkyl means aryl-alkyl wherein aryl and alkyl is as defined above.

Exemplary of organic acid addition salts according to the invention arethose with maleic, fumaric, benzoic, ascorbic, succinic, oxalic,bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic,propionic, tartaric, salicylic, citric, gluconic, lactic, malic,mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic,glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophyllineacetic acids, as well as the 8-halotheophyllines, for example8-bromotheophylline. Exemplary of inorganic acid addition saltsaccording to the invention are those with hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, and nitric acids. The acid additionsalts of the invention are preferably pharmaceutically acceptable saltsformed with non-toxic acids.

Further, the compounds of this invention may exist in unsolvated as wellas in solvated forms with pharmaceutically acceptable solvents such aswater, ethanol and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thisinvention.

Some of the compounds of the present invention contain chiral centresand such compounds exist in the form of isomers (i.e. enantiomers). Theinvention includes all such isomers and any mixtures thereof includingracemic mixtures.

Racemic forms can be resolved into the optical antipodes by knownmethods, for example, by separation of diastereomeric salts thereof withan optically active acid, and liberating the optically active aminecompound by treatment with a base. Another method for resolvingracemates into the optical antipodes is based upon chromatography on anoptically active matrix. Racemic compounds of the present invention canthus be resolved into their optical antipodes, e.g., by fractionalcrystallization of d- or I-(tartrates, mandelates, or camphorsulphonate)salts for example. The compounds of the present invention may also beresolved by the formation of diastereomeric derivatives.

Additional methods for the resolution of optical isomers, known to thoseskilled in the art, may be used. Such methods include those discussed byJ. Jaques, A. Collet, and S. Wilen in “Enantiomers, Racemates, andResolutions”, John Wiley and Sons, New York (1981).

Optically active compounds can also be prepared from optically activestarting materials.

The compounds of the invention can be prepared by one of the followingmethods comprising:

a) reducing the carbonyl groups of a compound of formula

 wherein R¹-R³, R¹², R¹⁴-R¹⁷, X, Y, Z, W, and the dotted line are asdefined above;

b) alkylating an amine of formula

 wherein R¹-R³, X, Y, Z, W, and the dotted line are as defined abovewith a reagent of formula G—CH₂CH₂—A wherein A is as defined above and Gis a suitable leaving group such as halogen, mesylate, or tosylate;

c) reductive alkylation of an amine of formula

 wherein R¹-R³, X, Y, Z, W, and the dotted line are as defined abovewith a reagent of formula B—CH₂—A, wherein A is as defined above and Bis either an aldehyde or a carboxylic acid group;

d) reducing the double bond of indoles of formula

 wherein R¹-R³, X, Y, Z, W and the dotted line are as defined above andA′ is a group of formula (II), (III), or (IV) as above in which thedotted line represents a bond, in order to obtain the corresponding2,3-dihydroindole derivatives;

e) reducing the double bond of the tetrahydropyridines of formula

 wherein R¹-R³, A, X, Y, and Z are as previously defined, in order toobtain the corresponding piperidine derivatives;

f) treating a compound of general formula (I) wherein Y is —CR⁶═CR⁷—, orwherein X and Y together form a group —CR⁴═CR⁵—, or —CR⁴═CR⁵—CR⁶R⁷ witha reducing agent in order to reduce the double bond, thereby obtaining acorresponding reduced ring system;

g) reductive removal of one or more of the substituents R¹-R³ or R¹²-R¹⁷in a compound of general formula (I) in which one or more of thesesubstituents are selected from chloro, bromo, or iodo;

h) dialkylating an amine of formula

 wherein R¹-R³, X, Y and Z is as defined above with a reagent of formula

 wherein A is as defined above and G is a suitable leaving group such ashalogen, mesylate, or tosylate;

i) dialkylating an amine of formula

 wherein A is as defined above with a reagent of formula

 wherein R¹-R³, X, Y, Z and W is as defined above and G is a suitableleaving group such as halogen, mesylate, or tosylate; or

j) alkylating or acylating the indole nitrogen atom of compounds offormula

 wherein R¹-R³, X, Y, Z, W, and the dotted line are as defined above,and A″ is a group selected from a group of formula (III), or (IV) asabove in which R¹¹ is hydrogen with alkylating or acylating reagents offormula R¹¹—G, wherein G is suitable a leaving group such as halogen,mesylate, or tosylate and R¹¹ is as defined above but not hydrogen;

whereupon the compounds of formula (I) are isolated as the free base orin the form of an acid addition salt thereof.

The reduction according to method a) is preferably carried out in aninert organic solvent such as diethyl ether or tetrahydrofuran in thepresence of lithium aluminium hydride at reflux temperature. Startingcompounds of formula (V) are generally prepared from reagents of formula(VI), 1,3-unsubstituted indoles, and oxalyl chloride as described in theexamples which follow.

The alkylation according to method b) is conveniently performed in aninert organic solvent such as a suitably boiling alcohol or ketone,preferably in the presence of a base (potassium carbonate ortriethylamine) at reflux temperature.

Arylpiperazine derivatives of formula (VI) are conveniently preparedfrom the corresponding arylamine according to the method described byMartin et al, J. Med. Chem., 1989, 32, 1052, or the method described byKruse et al, Rec. Trav. Chim. Pays-Bas, 1988, 107, 303. The startingarylamines are either commercially available or are well-described inthe literature.

Aryltetrahydropyridine derivatives of formula (VI) are known fromliterature, cf. U.S. Pat. No. 2,891,066; McElvain et al, J. Amer. Chem.Soc. 1959, 72, 3134. Conveniently, the corresponding arylbromide islithiated with BuLi followed by addition of 1-benzyl-4-piperidone.Subsequent treatment with acid gives theN-benzyl-aryltetrahydropyridine. The benzyl group can be removed bycatalytic hydrogenation or by treatment with e.g. ethyl chloroformate togive the corresponding ethyl carbamate followed by acidic or alkalinehydrolysis. The starting arylbromides are either commercially availableor well-described in the literature.

Reagents of formula G—CH₂CH₂—A are either commercially available or canbe prepared by literature methods, e.g. from the corresponding aceticacid derivative by reduction to the 2-hydroxyethyl derivative andconversion of the hydroxy group to the group G by conventional methods.

The reductive alkylation according to method c) is performed by standardliterature methods. The reaction can be performed in two steps, i.e.coupling of (VI) and the reagent of formula B—CH₂—A by standard methodsvia the carboxylic acid chloride or by use of coupling reagents such ase.g. dicyclohexylcarbodiimide followed by reduction of the resultingamide with lithium aluminium hydride. The reaction can also be performedby a standard one-pot procedure. Carboxylic acids or aldehydes offormula B—CH₂—A are either commercially available or described in theliterature.

Reduction of the indole double bond according to method d) isconveniently performed by treatment with diborane or a diboraneprecursor such as the trimethylamine or dimethylsulfide complex in aninert solvent such as e.g. tetrahydrofuran or dioxane from 0° C. toreflux temperature followed by acid catalyzed hydrolysis of theintermediate borane derivative. The reduction can alternatively beperformed by treatment with sodium cyanoborohydride in trifluoroaceticacid.

Reduction of the double bonds according to methods e) and f) is mostconveniently perfomed by hydrogenation in an alcohol in the presence ofa noble metal catalyst, such as e.g. platinum or palladium.

The removal of halogen substituents according to method g) isconveniently performed by catalytic hydrogenation in an alcohol in thepresence of a palladium catalyst or by treatment with ammonium formatein an alcohol at elevated temperatures in the presence of a palladiumcatalyst.

The dialkylation of amines according to methods h) and i) is mostconveniently performed at elevated temperatures in an inert solvent suchas e.g. chlorobenzene, toluene, N-methylpyrrolidone, dimethylformamide,or acetonitrile. The reaction might be performed in the presence of basesuch as e.g. potassium carbonate or triethylamine. Starting materialsfor processes h) and i) are commercially available or can be preparedfrom commercially available materials using conventional methods.

The N-alkylation according to method j) is performed in an inert solventsuch as e.g. an alcohol or ketone at elevated temperatures in thepresence of base, e.g. potassium carbonate or triethylamine at refluxtemperature. Alternatively, a phase-transfer reagent can be used.

The following examples will illustrate the invention further. They are,however, not to be construed as limiting.

EXAMPLES

Halogen-, methyl-, or methoxy substituted indoles used as described inExample 1 are commercially available.

Substituted 2-(1-indolyl)acetic acids used as described in Example 3 areprepared from the corresponding substituted indole and ethylbromoacetate by conventional methods.

Substituted 3-(2-bromoethyl)indoles used as described in Example 2 areprepared from the corresponding in 2-(1-indolyl)acetic acid ester byreduction to the alcohol with lithium aluminium hydride and subsequenttreatment with tetrabromomethane/triphenylphosphine according tostandard literature methods.

Arylpiperazines used as described in Examples 1, 2, and 3 are preparedfrom the corresponding arylamine according to the method described byMartin et al, J. Med. Chem. 32 (1989) 1052, or the method described byKruse et al, Rec. Trav. Chim. Pays-Bas 107 (1988) 303.

The starting arylamines are either commercially available or aredescribed in the literature as follows:

The synthesis of 5-amino-1,4-benzodioxane is described by Dauksas et al,Zh. Org. Khim. 3 (1967) 1121. The corresponding chlorinated derivativesare made in a similar manner.

The synthesis of 7-amino-2,3-dihydrobenzofuran is described in U.S. Pat.Appl. Ser. No. 4,302,592.

The synthesis of 7-amino-benzofuran is described by Van Wijngaarden etal, J. Med. Chem. 31 (1988) 1934.

The synthesis of 7-amino-benzo[b]thiophene is described by Boswell etal, J. Heterocycl. Chem. 5 (1968) 69.

7-amino-2,3-dimethylbenzofuran and the corresponding 5-chloro and5-methyl derivatives are prepared according to Ger. Offen. DE 3526510.

4-Amino-benzothiopyran were prepared according to Eur. Pat. Appl. EP79683.

8-Amino-6-chloro-2,2-dimethylebenzopyran was prepared by conventionalnitration of 6-chloro-2,2-dimethylebenzopyran (prepared according toBolzoni et al, Angew. Chem. 90 (1978)727-) with subsequent reduction ofthe obtained 8-nitro derivative. In a similar manner7-amino-5-chloro-3,3-dimethylbenzofuran was obtained from5-chloro-3,3-dimethylbenzofuran (prepared according to Eur. Pat. Appl.EP 7719 800206). The corresponding dechloro derivatives were obtained bytreatment with hydrogen gas in the presence of a nobel metal catalystaccording to standard procedures.

Aryl tetrahydropyridine derivatives are known from literature (cf. U.S.Pat. No. 2,891,066 or McElvain et al, J. Amer. Chem. Soc. 72 (1959)3134). Most conveniently, the corresponding aryl bromide is lthiatedwith BuLi followed by addition of 1-benzyl-4-piperidone. Subsequenttreatment with mineral acid or trifluoroacetic acid gives theN-benzyl-aryltetrahydropyridine. The benzyl group can be removes bycatalytic hydrogenation or by treatment e.g. ethyl chloroformate to thecorresponding ethyl carbamate followed by acidic or alkaline hydrolysis.The corresponding piperidine derivatives can be obtained by reductiveremoval of the double bond of the tetrahydropyridine ring. All theseprocedures are well-known to a person skilled in the art. The startingaryl bromides are well-described in the literature. In this manner4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydropyridine,4-(2,3-dihydro-2,2-dimethylbenzofuran-7-yl)-1,2,3,6-tetrahydropyridine,4-(2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydropyridine,4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridine, and the correspondingpiperidines were obtained.

Melting points were determined on a Buchi SMP-20 apparatus and areuncorrected. Mass spectra were obtained on a Quattro MS—MS system fromVG Biotech, Fisons Instruments The MS—MS system was connected to an HP1050 modular HPLC system. A volume of 20-50 μL of the sample (10 μg/mL)dissolved in a mixture of 1% acetic acid in acetonitrile/water 1:1 wasintroduced via the autosampler at a flow of 30 μL/min into theelectrospray source. Spectra were obtained at two standard sets ofoperating conditions One set to obtain molecular weight information(MH+) (21 eV) and the other set to induce fragmentation patterns (70 eV)The background was subtracted. The relative intensities of the ions areobtained from the fragmentation pattern. When no intensity is indicatedfor the Molecular Ion (MH+) this ion was only present under the firstset of operating conditions. 1H NMR spectra were recorded of all novelcompounds at 250 MHZ on a Bruker AC₂₅₀ or at 500 MHz on a Bruker DRX500. Deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) wereused as solvents. TMS was used as internal reference standard. Chemicalshifts are expressed as ppm values. The following abbreviations are usedfor multiplicity of NMR signals: s=singlet, d=doublet, t=triplet,q=quartet, qui=quintet, h=heptet, dd=double doublet, dt=double triplet,dq=double quartet, tt=triplet of triplets, m=multiplet. NMR signalscorresponding to acidic protons are generally omitted. Content of waterin crystalline compounds was determined by Karl Fischer titration.Standard workup procedures refer to extraction with the indicatedorganic solvent from proper aqueous solutions, drying of combinedorganic extracts (anhydrous MgSO₄ or NaSO₄), filtering, and evaporationof the solvent in vacuo. For column chromatography silica gel of typeKieselgel 60, 230-400 mesh ASTM was used.

Example 13-[2-[4-(1,4-Benzodioxan-5-yl)Piperazin-1-yl]Ethyl]-5-Chloro-1H-IndoleOxalate, 1a

A solution of 5-chloroindole (5.0 g) in diethyl ether (130 mL) wascooled to 0° C. under a nitrogen atmosphere followed by dropwiseaddition of a solution of oxalyl chloride (4.6 g) in diethyl ether (20mL). After stirring for 16 h, the crystalline product,2-(5-chloro-1H-indol-3-yl)-2-oxoacetyl chloride was collected byfiltration (7.2 g).

A solution of this product (2.0 g) in dry tetrahydrofuran (25 mL) wasadded dropwise to a mixture of 1-(1,4-benzodioxan-5-yl)piperazine (1.2g) and triethylamine (7.5 mL) in tetrahydrofuran (75 mL) at roomtemperature. The mixture was stirred for 16 h followed by filtration andremoval of solvent in vacuo giving crude3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]-1,2-dioxoethyl]-5-chloro-1H-indoleas a solid. This product was dissolved in tetrahydrofuran (25 mL) andadded dropwise to a suspension of lithium aluminium hydride (2.1 g) intetrahydrofuran at room temperature under a nitrogen atmosphere. Afterreflux for 3.5 h, the reaction was quenched with aq. sodium hydroxidefollowed by standard workup with ethyl acetate. The resulting oil waspurified by flash chromatography (eluent: heptane/ethanol/ethylacetate/triethylamine 15:2:2:1). The oxalate salt was obtained from anacetone solution by addition of oxalic acid and recrystallized frommethanol/tetrahydrofuran (1:5) giving 0.8 g of 1a. Mp: 224-28° C. ¹H NMR(DMSO-d₆): 3.05 (t, 2H); 3.10-3.50 (m, 10H); 4.15-4.30 (m, 4H); 6.50 (d,1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.10 (d, 1H); 7.30 (s, 1H); 7.40 (d,1H); 7.65 (s, 1H); 11.15 (s, 1H). MS m/z (%): 398 (MH+, 9%), 233 (100%),221 (29%), 218 (19%), 178 (59%).

The following compounds were prepared analogously:

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-bromo-1H-indoleoxalate, 1b, mp 236-40° C. ¹H NMR (DMSO-d₆): 3.10 (t, 2H); 3.15-3.45 (m,10H); 4.15-4.30 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H); 7.20(d, 1H); 7.30 (s, 1H); 7.35 (d, 1H); 7.80 (s, 1H); 11.20 (s, 1H). MS m/z(%): 444 (MH+, 5%), 442 (5%), 233 (80%), 224 (21%), 222 (22%), 221(25%), 218 (23%), 190 (19%), 70 (100%).

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-2-methyl-1H-indoleoxalate, 1c, mp 205-8° C. ¹H NMR (DMSO-d₆): 2.35 (s, 3H); 2.95-3.15 (m,4H); 3.15-3.45 (m, 8H); 4.15-4.30 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H);6.75 (t, 1H), 6.95 (t, 1H); 7.00 (t, 1H); 7.25 (d, 1H); 7.50 (d, 1H);10.85 (s, 1H). MS m/z (%): 378 (MH+, 5%), 233 (9%), 221 (7%), 218 (5%),158 (100%).

6-Chloro-3-[2-[4-(2,2,5-trimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl]ethyl]-1H-indolefumarate, 1d, mp 232-37° C. ¹H NMR (DMSO-d₆): 1.40 (s, 6H); 1.65-1.85(m, 4H); 2.20 (s, 3H); 2.30 (t, 2H); 2.60 (t, 2H); 2.70-2.85 (m, 3H);2.90 (s, 3H); 3.10-3.30 (m, 2H); 6.60 (s, 2H); 6.70 (s, 1H); 6.80 (s,1H); 7.00 (d, 1H); 7.20 (s, 1H); 7.35 (s, 1H); 7.55 (d, 1H); 10.95 (s,1H). MS m/z (%): 423 (MH+, 11%), 258 (100%), 178 (14%), 70 (41%).

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-4-chloro-1H-indoleoxalate, 1e, mp 210-18° C. ¹H NMR (DMSO-d₆): 3.10-3.50 (m, 12H);4.10-4.30 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H); 7.00 (d,1H); 7.05 (t, 1H); 7.30-7.40 (m, 2H); 11.40 (s, 1H). MS m/z (%): 398(MH+, 10%), 233 (100%), 221 (47%), 218 (18%), 180 (25%), 178 (84%).

6-Chloro-3-[2-[4-(2,2,-dimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl]ethyl]-1H-indoleoxalate, 1f, mp 190-93° C. ¹H NMR (DMSO-d₆): 1.40 (s, 6H); 1.75-.1.95(m, 4H), 2.50-2.70 (m, 2H); 2.70-2.80 (m, 1H); 2.85-3.05 (m, 6H);3.25-3.40 (m, 2H); 6.75 (t, 1H); 6.95 (d, 1H); 6.95-7.10 (m, 2H); 7.25(s, 1H); 7.40 (s, 1H); 7.55 (d, 1H); 11.00 (s, 1H).). MS m/z (%): 409(MH+, 6%), 244 (100%), 232 (9%), 178 (16%).

6-Chloro-3-[2-[4-(2,2,-dimethyl-2,3,-dihydrohydrobenzofuran-7-yl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl]-1H-indole oxalate, 1g, mp 200-4° C. ¹HNMR (DMSO-d₆): 1.40 (s, 6H); 2.70-2.80 (m, 2H); 3.00 (s, 2H); 3.15 (t,2H); 3.30 (t, 2H); 3.35-3.50 (m, 2H); 3.85-4.00 (m, 2H); 6.35 (s, 1H);6.85 (t, 1H); 7.00 (d, 1H); 7.05-7.15 (m, 2H); 7.30 (s, 1H); 7.40 (s,1H); 7.60 (d, 1H); 11.15 (s, 1H). MS m/z (%): 407 (MH+, 2%), 207 (8%),180 (33%), 178 (100%).

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indoleoxalate, 1h, mp 224-26° C. ¹H NMR (DMSO-d₆): 3.10 (t, 2H); 3.10-3.50 (m,10H); 4.15-4.35 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H); 6.95(t, 1H); 7.30 (s, 1H); 7.30-7.50 (m, 2H); 11.10 (s, 1H) MS m/z (%): 382(MH+, 9%), 233 (78%), 221 (30%), 218 (22%), 190 (20%),162 (97%), 70(100%).

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-y]ethyl]-5-methoxy-1H-indolehemioxalate, 1i, mp 189-96° C. ¹H NMR (DMSO-d₆): 3.00 (t, 2H); 3.05-3.30(m, 10H); 3.80 (s, 3H); 4.15-4.35 (m, 4H); 6.50 (d, 1H); 6.55 (d, 1H);6.70-6.80 (m, 2H); 7.10 (s, 1H); 7.15 (s, 1H); 7.25 (d, 1H); 10.70 (s,1H). MS m/z (%): 394 (MH+, 7%), 233 (79%), 218 (21%), 190 (21%), 174(61%), 70 (100%).

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-methyl-1H-indolehemifumarate, 1j, mp 147-54° C. ¹H NMR (DMSO-d₆): 2.40 (s, 3H);2.60-2.80 (m, 6H); 2.85 (t, 2H); 2.95-3.15 (m, 4H); 4.15-4.30 (m, 4H);6.45 (d, 1H); 6.50 (d, 1H); 6.60 (s, 1H); 6.70 (t, 1H); 6.90 (d, 1H);7.10 (s, 1H); 7.20 (d, 1H); 7.30 (s, 1H); 10.65 (s, 1H).

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-methyl-1H-indolehemifumarate, 1k, mp 204-7° C. ¹H NMR (DMSO-d₆): 2.35 (s, 3H); 2.60-2.80(m, 6H); 2.90 (t, 2H); 2.95-3.15 m, 4H); 4.10-4.30 (m, 4H); 6.45 (d,1H); 6.50 (d, 1H); 6.60 (s, 1H); 6.70 (t, 1H); 6.80 (d, 1H); 7.05 (s,1H); 7.10 (s, 1H); 7.40 (d, 1H); 10.60 (s, 1H).

6-Chloro-3-[2-[4-(7-chloro-1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indoleoxalate, 1l, mp 237-38° C. ¹H NMR (DMSO-d₆): 3.00-3.15 (m, 2H);3.15-3.40 (m, 10H); 4.20 (s, 4H); 6.50 (d, 1H); 6.65 (d, 1H); 7.00 (dd,1H); 7.25 (d, 1H); 7.40 (d, 1H); 7.60 (d, 1H); 10.95 (s, 1H). MS m/z(%): 432 (MH+, 3%), 267 (42%), 252 (12%), 224 (10%),178 (27%), 70(100%).

6-Chloro-3-[2-[4-(6-Chloro-1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indoleoxalate, 1m, mp 216-17° C. ¹H NMR (DMSO-d₆): 2.60 (t, ?H); 2.85 (t, 2H);3.10 (b, 4H); 3.30 (s, 4H); 4.15-4.30 (m, 4H); 6.15 (d, 1H); 6.35 (d,1H); 7.00 (dd, 1H); 7.20 (d, 1H); 7.35 (d, 1H); 7.55 (d, 1H); 10.95 (s,1H). MS m/z (%): 432 (MH+, 2%), 267 (47%), 252 (16%), 224 (16%), 178(30%), 70 (100%).

5-Chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indoleoxalate, 1n, mp 134-38° C. ¹H NMR (DMSO-d₆): 2.65-2.80 (m, 6H); 2.90 (t,2H); 3.00-3.25 (m, 6H); 4.50 (t, 2H); 6.60 (s, 1H); 6.65 (d, 1H); 6.75(t, 1H); 6.85 (d, 1H); 7.05 (d, 1H); 7.25 (s, 1H); 7.35 (d, 1H); 7.60(s, 1H); 11.05 (s, 1H). MS m/z (%): 382 (MH+), 217 (39%), 205 (17%), 178(38%), 143 (11%), 70 (100%).

6-Chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indoleoxalate, 1o, mp 205-7° C. ¹H NMR (DMSO-d₆): 2.60-2.75 (m, 6H); 2.90 (t,2H); 3.00-3.20 (m, 6H); 4.50 (t, 2H); 6.60 (s, 1H); 6.65 (d, 1H); 6.75(t, 1H); 6.80 (d, 1H); 6.95 (d, 1H); 7.20 (s, 1H); 7.35 (s, 1H); 7.55(d, 1H); 10.95 (s, 1H). MS m/z (%): 382 (MH+), 217 (33%), 202 (18%) 70(100%).

3-[2-[4-(2,3-Dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indoleoxalate, 1p, mp 145-49° C. ¹H NMR (DMSO-d⁶): 2.65-2.85 (m, 6H); 2.90 (t,2H); 3.00-3.20 (m, 6H); 4.50 (t, 2H); 6.60 (s, 1H); 6.65 (d, 1H); 6.75(t, 1H); 6.85 (d, 1H); 6.90 (t, 1H); 7.25 (s, 1H); 7.25-7.35 (m, 2H);10.95 (s, 1H). MS m/z (%): 366 (MH+, 4%), 217 (31%), 205 (18%), 174(16%), 162 (81%) 70 (100%).

3-[2-[4-(Benzothiophen-7-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,oxalate, 1 q, mp 175.2-176.6° C. ¹H NMR (DMSO-d₆): 3.10 (m, 2H), 3.26(m, 2H), 3.38-3.36 (m, 6H), 7.05 (d, 1H), 7.09 (d, 1H), 7.33 (s, 1H),7.40-7.37 (m, 3H), 7.47 (d, 1H), 7.62 (d, 1H), 7.69 (s, 1H), 7.76 (d,1H). MS m/z 398.1 (MH+, 1.1% (³⁷Cl)), 396.1 (MH+, 2.8% (³⁵Cl)), 230.9(1005), 177.8 (58%), 69.8 (50.8%).

3-[2-[4-(Benzothiopyran-8-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,1r, mp 152-153° C. ¹H NMR (CDCl₃): 2.08 (m, 2H), 2.75 (m, 6H), 2.83 (m,2H), 2.98 (m, 4H), 3.05 (m, 2H), 6.80 (d, 1H), 6.99-6.94 (m, 2H), 7.08(s, 1H), 7.14 (d, 2H), 7.26 (d, 1H), 7.59 (s, 1H), 8.00 (s, 1H). MS m/z412.3 (MH+, 100% (³⁵Cl)), 414.5 (MH+, 63. % (³⁷ Cl)), 247.1 (23.7%).

3-[2-[4-(Benzothiopyran-8-yl)piperazin-1-yl]ethyl]-5-bromo-1H-indole,1s, mp 166-167 ° C. ¹H NMR (CDCl₃): 2.04 (m, 2H), 2.75 (m, 6H), 2.82 (m,2H), 2.98 (m, 4H), 3.05 (m, 4H), 6.81 (d, 1H), 6.98-6.93 (m, 2H), 7.05(s, 1H), 7.21 (d, 1H), 7.26 (d, 1H), 7.76 (s, 1H), 8.02 (s, 1H). MSm/z458.4 (MH+, 21.7% (⁸¹ Br), 456.3 (MH+, 23.9% (⁷⁹Br), 232.0 (58.7%),143.1 (100%)

3-[2-[4-(Benzothiopyran-8-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,1t, mp 178-179° C. ¹H NMR (CDCl₃):2.07 (m, 2H), 2.75 (m, 6H), 2.83 (m,2H), 2.98 (m, 4H), 3.04 (m, 4H), 6.80 (d, 1H), 6.98-6.92 (m, 2H), 7.04(s, 1H), 7.08 (d, 1H), 7.33 (s, 1H), 7.52 (d, 1H), 7.95 (s, 1H). MS m/z412.3 (MH+, 31.8% (³⁵Cl)), 247.3 (81.8%), 232.0 (63.9%), 178.1(63.6%),143.1 (100%).

3-[2-[4-(Benzofuran-7-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole, 1u,mp 202-4° C. ¹H NMR (DMSO-d₆): 2.65-2.85 (m, 6H); 2.90 (t, 2H);3.20-3.40 (m, 4H); 6.60 (s, 1H); 6.80 (d, 1H); 6.90 (d,1H); 7.00 (d,1H); 7.05-7.30 (m, 3H); 7.40 (d, 1H); 7.55 (d, 1H); 7.95 (d,1H); 11.00(s, 1H). MS m/z (%): 380 (MH+, 4%), 215 (100%), 200 (12%), 178 (36%),172 (20%).

3-[2-[4-(1,4-Benzodioxan-5-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-6-chloro-1H-indoleoxalate, 1v, mp 240-47° C. ¹H NMR (DMSO-d₆): 2.70 (s, 2H); 3.10 (t, 2H);3.20-3.70 (m, 4H); 3.80 (s, 2H); 4.25 (s, 4H); 5.85 (s, 1H); 6.75 (t,1H); 6.80 (d, 2H); 7.05 (d, 1H); 7.30 (s, 1H); 7.40 (s, 1H); 7.60 (d,1H); 11.10 (s, 1H). MS m/z (%): 395 (MH+, 1%), 178 (100%).

6-Chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-1H-indoleoxalate, 1x, mp 211-14° C. ¹H NMR (DMSO-d₆): 2.75 (s, 2H); 3.05-3.15 (m,2H); 3.20 (t, 2H), 3.25-3.50 (m, 4H); 3.85 (s, 2H), 4.55 (t, 2H); 6.30(s, 1H); 6.85 (t, 1H); 7.00 (d, 1H); 7.10 (d, 1H); 7.15 (d, 1H); 7.30(s, 1H); 7.40 (s, 1H); 7.60 (d, 1H); 11.10 (s, 1H). MS m/z (%): 379(MH+, 3%),178 (100%).

3-[2-[4-(Benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-6-chloro-1H-indolehemifumarate, 1y, mp 214-20° C. ¹H NMR (DMSO-d₆): 2.65 (s, 2H);2.75-2.85 (m, 4H); 2.90-3.00 (m, 2H); 3.10-3.50 (m, 3H); 6.55 (s, 2H);6.90-7.00 (m, 2H), 7.15-7.30 (m, 3H); 7.35 (s, 1H); 7.50-7.60 (m, 2H);8.00 (s, 1H); 10.90 (s, 1H). MS m/z (%): 377 (MH+, 25%),178 (73%),143(22%).

3-[2-[4-(Benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-bromo-1H-indoleoxalate, 1z, mp 185-94° C. ¹H NMR (DMSO-d₆): 2.90 (s, 2H); 3.10-3.20 (m,2H); 3.25-3.55 (m, 4H), 3.95 (s, 2H); 6.60 (s, 1H); 7.00 (s, 1H); 7.20(d, 1H); 7.20-7.45 (m, 4H); 7.60 (d, 1H); 7.80 (s, 1H); 8.05 (s, 1H);11.20 (s, 1H). MS m/z (%): 423 (MH+(⁸¹Br), 22%), 421 (MH+(⁷⁹Br), 20%),224 (70%), 222(72%),143 (33%).

3-[2-[4-(Benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-fluoro-1H-indolehemioxalate, 1aa, mp 176-79° C. ¹H NMR (DMSO-d₆): 2.75 (s, 2H);2.90-3.25 (m, 6H); 3.65 (s, 2H); 6.60 (s, 1H); 6.85-6.95 (m, 1H); 7.00(s, 1H); 7.20-7.40 (m, 5H); 7.60 (d, 1H); 8.00 (s, 1H); 11.00 (s, 1H).MS m/z (%): 361 (MH+, 12%), 162(100%),115(13%).

3-[2-[4-(Benzofuran-7-yl)piperidin-1-yl]ethyl]-6-chloro-1H-indolehemifumarate, 1bb, mp 245-50° C. ¹H NMR (DMSO-d₆):1.85-2.00 (m, 4H);2.75 (t, 2H); 2.90 (t, 2H); 3.05 (tt, 1H); 3.25 (d, 2H); 6.55 (s, 2H);6.95 (s, 1H); 7.00 (d, 1H); 7.15-7.25 (m, 3H); 7.40 (s, 1H); 7.50 (d,1H); 7.55 (d, 1H); 8.00 (s, 1H); 10.95 (s, 1H). MS m/z (%): 379 (MH+,5%), 214 (10%), 178(20%), 143(100%).

3-[2-[4-(Benzofuran-7-yl)piperidin-1-yl]ethyl]-5-fluoro-1H-indoleoxalate, 1 cc, mp 191-94° C. ¹H NMR (DMSO-d₆): 2.05-2.25 (m, 4H);3.05-3.20 (m, 4H); 3.20-4.40 (m, 3H), 3.60-3.70 (m, 2H); 6.90-7.00 (m,2H), 7.15-7.25 (m, 2H); 7.35-7.45 (m, 3H); 7.55 (d, 1H), 8.00 (s, 1H);11.05 (s, 1H). MS m/z (%). 363 (MH+, 5%), 214 (9%), 161 (10%),143 (24%).

3-[2-[4-(Benzofuran-7-yl)piperidin-1-yl]ethyl]-5-bromo-1H-indoleoxalate, 1dd, mp 153-57° C. ¹H NMR (DMSO-d₆): 2.05-2.20 (m, 4H);3.05-3.20 (m, 4H); 3.20-3.40 (m, 3H); 3.70 (d, 2H); 6.95 (s, 1H);7.15-7.25 (m, 3H); 7.30-7.40 (m, 2H); 7.55 (d, 1H); 7.80 (s, 1H); 8.00(s, 1H); 11.20 (s, 1H). MS m/z (%): 423 (MH+, 36%), 224 (27%), 202(45%), 143 (27%), 117 (18%).

Example 2 3-[2-[4-(1,4-Benzodioxan-5-yl)Piperazin-1-yl]Ethyl]-1H-IndoleHemifumarate, 2a

A mixture of 3-(2-bromoethyl)-1H-indole (1.5 g),1-(1,4-benzodioxan-5-yl)piperazine (1.2 g), potassium carbonate (1.9 g),and potassium iodide (0.1 g) in methylisobutyl ketone (100 mL) wasrefluxed for 16 h. Standard workup with ethyl acetate gave an oil whichwas purified by flash chromatography (eluent: heptane/ethanol/ethylacetate/triethylamine 15:2:2:1). The fumarate salt was obtained from anethanol solution by addition of fumaric acid. Recrystallization fromethanol gave the hemifumarate 2a (0.9 g). Mp: 204-7° C. ¹H NMR(DMSO-d₆): 2.60-2.80 (m, 6H); 2.90 (t, 2H); 2.95-3.10 (m, 4H); 4.15-4.30(m, 4H); 6.50 (d, 1H); 6.55 (d, 1H); 6.60 (s, 1H); 6.75 (t, 1H); 7.00(t, 1H); 7.10 (t, 1H); 7.20 (s, 1H); 7.35 (d, 1H); 7.55 (d, 1H); 10.75(s, 1H). MS m/z (%): 364 (MH+, 5%), 233 (57%), 218 (21%), 190 (19%), 144(54%), 70 (100%).

1-Acetyl-3-[2-[4-(1,4-benzodioxan-4-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1H-indole,2b, mp 119-20° C. ¹H NMR (DMSO-d₆) 1.90 (d, 1H); 2.20 (s, 4H); 2.95-3.30(m, 11H); 3.40-3.50 (m, 1H); 3.75-3.85 (m, 1H); 4.20-4.30 (m, 4H); 6.45(dd, 1H); 6.55 (dd, 1H); 6.75 (t, 1H);7.00 (t, 1H);7.20 (t, 1H); 7.30(d, 1H); 8.05 (d, 1H). MS m/z (%): 408 (MH+, 54%), 233 (17%), 178(100%), 119 (20%).

Example 33-[2-[4-(1,4-Benzodioxan-5-yl)Piperazin-1-yl]Ethyl]-6-Chloro-1H-IndoleHemifumarate, 3a

A mixture of 2-(6-chloro-1H-indol-3-yl)acetic acid (2.0 g),1-(1,4-benzodioxan-5-yl)piperazine (3.6 g), N,N-dicyclohexylcarbodiimide(2.4 g), and 4-dimethylaminopyridine (0.2 g) in dry tetrahydrofuran (100mL) was stirred for 16 h at room temperature under a nitrogenatmosphere. Filtration and standard workup with methylene chloride gavean oil which was purified by flash chromatography (eluent: ethylacetate/heptane/methanol 16:3:1 giving3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]-2-oxoethyl]-6-chloro-1H-indoleas an oil (2.0 g).

The oil was dissolved in tetrahydrofuran (25 mL) and added dropwise to asuspension of lithium aluminium hydride (0.9 g) in dry tetrahydrofuran(50 mL) at room temperature followed by reflux for 3 h. Quench with 2 Maq. sodium hydroxide and standard workup gave the free base of 3a as anoil (1.9 g). The hemifumarate salt, 3a (1.0 g), was obtained from anethanol solution by addition af fumaric acid. Mp: 215-16° C. ¹H NMR(DMSO-d₆): 2.60-2.85 (m, 6H); 2.85-2.95 (m, 2H); 2.95-3.10 (m, 4H);4.10-4.30 (m, 4H); 6.45 (d, 1H); 6.50 (d, 1H); 6.60 (s, 1H); 6.70 (t,1H); 7.0 (dd, 1H); 7.25 (d, 1H); 7.40 (d, 1H); 7.55 (d, 1H); 10.95 (s,1H). MS m/z (%): 398 (MH+, 10%), 234 (13%), 233 (100%), 178 (12%).

The following compounds were prepared analogously:

3-[2-[4-(5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indolehemifumarate, 3b, mp 210-12° C. ¹H NMR (DMSO-d₆): 1.40 (s, 6H);2.55-2.75 (m, 6H); 2.80-3.00 (m, 4H); 3.05-3.20 (m, 4H); 6.60 (s, 1H);6.65 (d, 1H); 6.80 (d, 1H); 6.95 (t, 1H); 7.05 (t, 1H); 7.15 (d, 1H);7.35 (d, 1H); 7.55 (d, 1H); 10.70 (s, 1H). MS m/z (%): 410 (MH+, 18%),281 (32%), 279 (100%), 144 (39%).

6-Chloro-3-[2-[4-(5-chloro-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indolehemifumarate, 3c, mp 130-32° C. ¹H NMR (DMSO-d₆): 1.25 (s, 6H);2.55-2.70 (m, 6H); 2.85 (t, 2H); 3.00-3.20 (m, 4H); 4.25 (s, 2H); 6.60(s, 1H); 6.65 (s, 1H); 6.85 (s, 1H); 7.00 (d, 1H); 7.20 (s, 1H); 7.35(s, 1H); 7.55 (d, 1H); 10.90 (s, 1H). MS m/z (%): 446 (8%), 444 (MH+,11%), 281 (34%), 280 (16%), 279 (100%), 178 (15%).

6-Chloro-3-[2-[4-(6-chloro-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-8-yl)piperazin-1yl]ethyl]-1H-indolefumarate, 3d, mp 224-25° C. (¹H NMR (DMSO-d₆). 1.30 (s, 6H); 1.70 (t,2H); 2.60-2.75 (m, 8H); 2.90 (t, 2H); 2.95-3.10 (m, 4H), 6.60 (s, 1H);6.65 (d, 1H); 6.70 (d, 1H); 7.00 (d, 1H); 7.20 (s, 1H); 7.35 (s, 1H);7.55 (d, 1H); 10.95 (s, 1H). MS m/z (%) 458 (MH+, 11%), 295 (32%), 293(100%), 259 (11%), 178 (14%)

6-Chloro-3-[2-[4-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indolefumarate, 3e, mp 165-67° C. ¹H NMR (DMSO-d₆): 1.40 (s, 6H); 2.65-280 (m,6H); 290 (t, 2H); 2.95 (s, 2H); 3.00-3.20 (m, 4H); 6.60 (s, 1H); 6.65(d, 1H); 6.70 (t, 1H); 6.75 (d, 1H); 7.00 (d, 1H); 7.20 (s, 1H); 7.35(s, 1H); 7.55 (d, 1H). MS m/z (%): 410 (MH+, 6%), 245 (67%), 209 (39%),178 (8%), 127 (51%), 45 (100%).

1-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indoleoxalate, 3f, mp 234-35° C. ¹H NMR (DMSO-d₆): 2.85 (s, 4H); 2.95-3.15 (m,6H); 4.15-4.30 (m, 4H); 4.40 (t, 2H); 6.45-6.55 (m, 3H); 6.70 (t, 1H);7.05 (d, 1H); 7.45 (d, 1H); 7.55 (d, 1H); 7.70 (s, 1H). MS m/z (%): 398(MH+, 45%), 218 (100%),178 (50%).

1-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indoleoxalate, 3g, mp 234-35° C. ¹H NMR (DMSO-d₆): 2.85 (s, 4H); 2.95-3.15 (m,6H); 4.15-4.30 (m, 4H); 4.45 (t, 2H); 6.40-6.50 (m, 2H); 6.55 (d, 1H);6.70 (t, 1H); 7.15 (d, 1H); 7.50 (s, 1H); 7.55-7.65 (m, 2H). MS m/z (%):398 (MH+; 44%), 218 (100%), 178 (62%).

1-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indoleoxalate, 3h, mp 230-31° C. ¹H NMR (DMSO-d₆): 2.90 (s, 4H); 2.95-3.20 (m,6H); 4.15-4.30 (m, 4H); 4.45 (t, 2H); 6.40-6.50 (m, 2H); 6.55 (d, 1H);6.75 (t, 1H); 7.00 (t, 2H); 7.30 (d, 1H); 7.50 (s, 1H); 7.50-7.55 (m,1H). MS m/z (%): 382 (MH+, ?), 218 (63%),162 (100%).

1-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole oxalate,3i, mp 225-29° C. ¹H NMR (DMSO-d₆): 2.95 (s, 4H); 3.05-3.20 (m, 6H);4.10-4.30 (m, 4H); 4.45 (t, 2H); 6.40-6.50 (m, 2H); 6.55 (d, 1H); 6.75(t, 1H); 7.05 (t, 1H); 7.40 (s, 1H); 7.55 (t, 2H). MS m/z (%): 364 (MH+,100%), 218 (85%), 146 (80%).

1-[2-[4-(2,3-Dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indoleoxalate, 3j, mp 223-26° C. ¹H NMR (DMSO-d₆): 2.85 (s, 4H); 3.00 (t, 2H);3.05-3.20 (m, 6H); 4.40 (t, 2H); 4.50 (t, 2H); 6.45 (d, 1H); 6.65 (d,1H); 6.75 (t, 1H); 6.85 (d, 1H); 7.00 (t, 1H); 7.15 (t, 1H); 7.40 (d,1H), 7.55 (dd, 2H). MS m/z (%): 348 (MH+, 38%), 231 (50%), 201 (100%),174 (25%), 162 (41%), 146 (98%).

Example 43-[2-[4-(1,4-Benzodioxan-5-yl)Piperazin-1-yl]Ethyl]-2,3-Dihydro-1H-IndoleSesquioxalate, 4a

A solution of 2a (16 g) in trifluoroacetic acid (200 mL) was treated inportions with sodium borohydride (2×2.9 g, 1.5 hour interval) at roomtemperature followed by stirring for 2.5 hours at room temperature. Thereaction mixture was poured onto ice and made alkaline with aq. sodiumhydroxide followed by standard work-up. The resulting oil was purifiedby flash chromatography (eluent: heptane/ethylacetate/ethanol/triethylamine 15:2:2:1) giving the title base as ayellow oil (13.8 g). The title oxalate was as obtained from the freebase (1.4 g) as crystalline material from ethanol by addition of oxalicacid (0.9 g). Mp 145-50° C. ¹H NMR (DMSO-d₆): 1.75-1.85 (m, 1H);2.05-2.15 (m, 1H); 2.95-3.30 (m, 12H); 3.60 (t, 1H); 4.20 (d, 4H); 6.50(d, 2H); 6.60 (d, 2H); 6.75 (t, 1H); 6.95 (t, 1H); 7.10 (d, 1H). MS m/z(%): 366 (MH+, 10%), 221 (10%), 178 (14%), 150 (20%), 118 (100%).

The following compounds were prepared analogously:

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-5-fluoro-1H-indolehemioxalate, 4b, mp 201-5° C. ¹H NMR (DMSO-d₆): 1.60-1.80 (m, 1H);1.95-2.10 (m, 1H); 2.60-3.30 (m, 12H); 3.35 (t, 1H); 4.20 (d, 4H);6.35-6.55 (m, 3H); 6.15-6.25 (m, 2H); 6.90 (d, 1H). MS m/z (%): 384(MH+, 32%), 178 (28%), 150 (12%), 136 (100%).

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-2,3-dihydro-1H-indoleoxalate, 4c, mp 153-57° C. ¹H NMR (DMSO-d₆): 1.70-1.85 (m, 1H);2.05-2.20 (m, 1H); 2.85-3.05 (m, 2H); 3.05-3.35 (m, 10H); 3.60 (t, 2H);4.15-4.30 (m, 4H); 6.45-6.60 (m, 3H); 6.75 (t, 1H); 6.95 (dd, 1H); 7.10(d, 1H). MS m/z (%): 400 (MH+, 39%), 178 (39%), 152 (100%).

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-2,3-dihydro-1H-indoleoxalate, 4d, mp 185-88° C. ¹H NMR (DMSO-d₆): 1.75-1.85 (m, 1H);2.00-2.10 (m, 1H); 2.90-3.30 (m, 12H); 3.60 (t, 1H); 4.15-4.30 (m, 4H);6.45 (s, 1H); 6.50 (d, 1H); 6.55 (t, 2H); 6.75 (t, 1H); 7.05 (d, 1H) MSm/z (%): 400 (MH+, 14%), 221 (52%), 180 (22%), 152 (100%)

Example 53-[2-[4-(1,4-Benzodioxan-5-yl)Piperazin-1-yl]Ethyl]-1-Butyl-1H-IndoleOxalate, 5a

A solution of 2a (1.0 g) in dry tetrahydrofuran (50 mL) was addeddropwise to a suspension of sodium hydride (60% in mineral oil, 0.14 g)in tetrahydrofuran (25 mL) at room temperature. After stirring for 30min a solution of 1-bromobutane (0.85 g) in dry tetrahydrofuran (10 mL)was added dropwise. Stirring for 1 hour followed by standard work-upwith ethyl acetate gave an oil which was purified by flashchromatography (eluent: heptane/ethyl acetate/triethylamine 15:3:2). Theresulting oil was converted to the title oxalate salt (0.7 g) fromacetone by addition of oxalic acid. Mp 168-74° C. ¹H NMR (DMSO-d₆): 0.90(t, 3H); 1.25 (qv, 2H); 1.70 (qv, 2H); 3.05 (t, 2H); 3.15-3.40 (m, 8H);4.10 (t, 2H); 4.15-4.30 (m, 4H); 6.55 (d, 1H); 6.60 (d, 1H); 6.75 (t,1H); 7.05 (t, 1H); 7.15 (t, 1H); 7.25 (s, 1H); 7.45 (d, 1H); 7.60 (d,1H). MS m/z (%): 420 (MH+, 33%), 233 (39%), 200 (100%), 158 (36%).

The following compounds were prepared analogously:

1-Allyl-3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indoleoxalate, 5b, mp 187-90° C. ¹H NMR (DMSO-d₆): 3.05 (t, 2H); 3.10-3.40 (m,10H); 4.20 (d, 4H); 4.75 (d, 2H); 5.05 (d, 1H); 5.15 (d, 1H); 5.90-6.05(m, 1H); 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.05 (t, 1H); 7.15(t, 1H); 7.25 (s, 1H); 7.40 (d, 1H); 7.60 (d, 1H). MS m/z (%): 404 (MH+,38%), 233 (38%), 184 (43%), 120 (29%).

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-1-propargyl-1H-indoleoxalate, 5c, mp 168-72° C. ¹H NMR (DMSO-d₆): 3.00-3.30 (m, 12H); 3.40(t, 1H); 4.25 (d, 4H); 5.05 (d, 2H); 6.50 (d, 2H); 6.55 (d, 1H); 7.10(t, 1H); 7.20 (t, 1H); 7.30 (s, 1H); 7.50 (d, 1H); 7.65 (d, 1H). MS m/z(%): 402 (MH+, 52%), 233 (50%),182 (57%),167 (100%).

Example 63-[2-[4-(1,4-Benzodioxan-5-yl)Piperazin-1-yl]Ethyl]-2,3-Dihydro-1-Methyl-1H-IndoleOxalate, 6a

A solution of 4a (1.5 g) in dry tetrahydrofuran (50 mL) was addeddropwise to a suspension of sodium hydride (60% in mineral oil, 0.21 g)in tetrahydrofuran (25 mL) at room temperature. After stirring for 30min a solution of iodomethane (0.75 g) in dry tetrahydrofuran (25 mL)was added dropwise. Stirring for 1 hour followed by standard work-upwith ethyl acetate gave an oil which was purified by flashchromatography (eluent: heptane/ethyl acetate/triethylamine 15:3:2). Theresulting oil was converted to the title oxalate salt (0.3 g) fromacetone by addition of oxalic acid. Mp 155-65° C. ¹H NMR (DMSO-d₆)1.75-1.85 (m, 1H); 2.05-2.15 (m, 1H); 2.70 (s, 3H); 2.90-3.25 (m, 12H);3.40 (t, 1H); 4.15-4.30 (m, 4H); 6.45-6.55 (m, 3H); 6.65 (t, 1H); 6.75(t, 1H); 7.05 (t, 1H); 7.10 (d, 1H). MS m/z (%): 380 (MH+, 4%), 178(4%), 132 (53%).

The following compounds were prepared analogously:

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-1-benzyl-2,3-dihydro-1H-indoleoxalate, 6b, mp 158-65° C. ¹H NMR (DMSO-d₆): 1.75-1.85 (m, 1H);2.10-2.20 (m, 1H); 2.90-3.30 (m, 12H); 3.45 (t, 1H); 4.15-4.25 (m, 5H);4.35 (d, 1H); 6.50 (d, 1H); 6.55 (d, 1H); 6.65-6.70 (m, 2H); 6.75 (t,1H); 7.00 (t, 1H); 7.10 (d, 1H); 7.30 (t, 1H); 7.35 (s, 4H). MS m/z (%):456 (MH+, 19%), 236 (25%), 178 (100%), 130 (11%).

1-Allyl-3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1H-indoleoxalate, 6c, mp 133-36° C. ¹H NMR (DMSO-d₆): 1.75-1.85 (m, 1H);2.10-2.20 (m, 1H); 2.95-3.35 (m, 12H); 3.50 (t, 1H); 3.65 (dd, 1H); 3.75(dd, 1H); 4.25 (d, 4H); 5.15 (d, 1H); 5.30 (d, 1H); 5.85-5.95 (m, 1H);6.50 (d, 1H); 6.55 (d, 2H); 6.65 (t, 1H); 6.75 (t, 1H); 7.00 (t, 1H);7.10 (d, 1H). MS m/z (%): 406 (MH+, 15%), 178 (178%), 158 (24%), 130(31%), 117 (20%).

Example 71-Acetyl-3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indoleoxalate, 7a

A mixture of 2a (2.0 g), tetrabutylammonium hydrogen sulfate (0.2 g),sodium hydroxide (1.0 g), and methylene chloride (40 mL) was stirred for10 min followed by dropwise addition of a solution of acetyl chloride(0.97 g) in methylene chloride at room temperature. After stirring for 1hour water was added followed by standard work-up. The resulting oil waspurified by flash chromatography (eluent heptane/ethylacetate/ethanol/triethylamine 17:1:1) giving a yellow oil which wasconverted to the title oxalate salt (0.75 g) from acetone by addition ofoxalic acid. Mp 199-202° C. ¹H NMR (DMSO-d₆): 2.65 (s, 3H); 3.05 (t,2H); 3.15 (s, 10H); 4.20 (d, 2H); 4.25 (d, 2H); 6.50 (d, 1H); 6.55 (d,1H); 6.75 (t, 1H); 7.30-7.40 (m, 2H); 7.70 (d, 1H); 7.80 (s, 1H); 8.35(d, 1H) MS m/z (%):406 (MH+, 28%), 233 (44%), 218 (39%),144 (100%).

Pharmacological Testing

The affinity of the compounds of the invention to 5-HT_(1A) receptorswas determined by measuring the inhibition of binding of a radioactiveligand at 5-HT_(1A) receptors as described in the following test:

Inhibition of ³H-5-CT Binding to Human 5-HT_(1A) Receptors

By this method the inhibition by drugs of the binding of the 5-HT_(1A)agonist ³H-5-carboxamido tryptamine (³H-5-CT) to cloned human 5-HT_(1A)receptors stably expressed in transfected HeLa cells (HA7) (Fargin, A.et al, J. Biol. Chem., 1989, 264, 14848) is determined in vitro. Theassay was performed as a modification of the method described byHarrington, M. A. et al, J. Pharmacol. Exp. Ther., 1994, 268, 1098.Human 5-HT_(1A) receptors (40 μg of cell homogenate) were incubated for15 minutes at 37° C. in 50 mM Tris buffer at pH 7.7 in the presence of³H-5-CT. Non-specific binding was determined by including 10 μM ofmetergoline. The reaction was terminated by rapid filtration throughUnifilter GF/B filters on a Tomtec Cell Harvester. Filters were countedin a Packard Top Counter. The results obtained are presented in table 1:

TABLE 1 Inhibition of ³H-5-CT binding Compound No. IC₅₀ (nM) 1a 17 1b7.2 1c 2.5 1d 55 1e 11 1f 6.1 1g 2.8 1h 4.6 1i 6.9 1j 14 1k 2.0 1l 12 1m99 1n 8.2 2a 2.9 2b 13 1v 0.81 3a 1.2 3b 3.6 3d 21 4d 14 Pindolol* 100*reference compound

The compounds of the invention have also been tested for their effect onre-uptake of serotonin in the following test:

Inhibition of ³H-5-HT Uptake Into Rat Brain Synaptosomes

Using this method the ability of drugs to inhibit the accumulation of³H-5-HT into whole rat brain synaptosomes is determined in vitro. Theassay was performed as described by Hyttel, J., Psychopharmacology 1978,60, 13 The results obtained are presented in table 2:

TABLE 2 Inhibition of serotonin reuptake Compound No IC₅₀ (nM) 1a 5.0 1b2.8 1c 45 1d 36 1e 0.25 1f 5.9 1g 3.8 1h 1.7 1i 6.8 1j 3.5 1k 18 1l 7.71m 57 1n 2.1 1v 0.85 2a 3.5 2b 12 3a 5.3 3b 8.3 3d 15 4d 4.3 Paroxetine*0.29 *reference compound

The 5-HT_(1A) antagonistic activity of some of the compounds of theinvention has been estimated in vitro at cloned 5-HT_(1A) receptorsstably expressed in transfected HeLa cells (HA7). In this test 5-HT_(1A)antagonistic activity is estimated by measuring the ability of thecompounds to antagonize the 5-HT induced inhibition of forskolin inducedcAMP accumulation. The assay was performed as a modification of themethod described by Pauwels, P. J et al, Biochem. Pharmacol. 1993, 45,375. The results obtained are presented in table 3:

TABLE 3 Compound Antagonism of Inhibition of forskolin induced No. cAMPaccumulation IC₅₀ (nM) 1a 2900 1b 5000 1e 2400 1f 1800 1g 1800 1h 280 1i620 1j 980 1k 580 1n 1900 1o 3200 1t 5900 1u 2000 1v 3300 1x 3000 2a 1602b 250 3a 500 3c 2600 3d 2300 4d 890 6a 100 Pindolol* 270 *referencecompound

Some of the compounds of the invention have also been tested for theirin vivo effect on 5-HT_(1A) receptors in the assay described by Sánchez.C. Et al., Eur. J Pharmacol, 1996, 315, pp 245. In this testantagonistic effects of test compounds are determined by measuring theability of the test compounds to inhibit 5-MeO-DMT induced 5-HTsyndrome.

The compounds of the present invention possess valuable activity asserotonin re-uptake inhibitors and have antagonistic effect at 5-HT_(1A)receptors. The compounds of the invention are therefore considereduseful for the treatment of diseases and disorders responsive to theinhibition of serotonin re-uptake and antagonistic activity at 5-HT_(1A)receptors. Diseases responsive to the inhibition of serotonin re-uptakeare well known in the art and include affective disorders, such asdepression, psychosis, anxiety disorders including general anxietydisorder, panic disorder, obsessive compulsive disorder, etc.

As explained above, the antagonistic activity at 5-HT_(1A) receptors ofthe compounds of the invention will counteract the negative feed backmechanism induced by the inhibition of serotonin reuptake and is therebyexpected to improve the effect of the serotonin reuptake inhibitingactivity of the compounds of the invention.

The compounds as claimed herein are therefore considered to beparticularly useful as fast onset of action medicaments for thetreatment of depression. The compounds may also be useful for thetreatment of depressions which are non-responsive to currently availableSSRI's.

Pharmaceutical Formulation

The pharmaceutical formulations of the invention may be prepared byconventional methods in the art. For example: Tablets may be prepared bymixing the active ingredient with ordinary adjuvants and/or diluents andsubsequently compressing the mixture in a conventional tablettingmachine. Examples of adjuvants or diluents comprise: corn starch, potatostarch, talcum, magnesium stearate, gelatine, lactose, gums, and thelike. Any other adjuvants or additives usually used for such purposessuch as colourings, flavourings, preservatives etc. may be used providedthat they are compatible with the active ingredients.

Solutions for injections may be prepared by dissolving the activeingredient and possible additives in a part of the solvent forinjection, preferably sterile water, adjusting the solution to desiredvolume, sterilization of the solution and filling in suitable ampules orvials Any suitable additive conventionally used in the art may be added,such as tonicity agents, preservatives, antioxidants, etc.

The pharmaceutical compositions of this invention or those which aremanufactured in accordance with this invention may be administered byany suitable route, for example orally in the form of tablets, capsules,powders, syrups, etc., or parenterally in the form of solutions forinjection. For preparing such compositions, methods well known in theart may be used, and any pharmaceutically acceptable carriers, diluents,excipients, or other additives normally used in the art may be used.

Conveniently, the compounds of the invention are administered in unitdosage form containing said compounds in an amount of about 0.01 to 1000mg The total daily dose is usually in the range of about 0.05-500 mg,and most preferably about 0.1 to 50 mg of the active compound of theinvention.

What is claimed is:
 1. An indole or 2,3-dihydro-indole derivative of theformula:

any of its enantiomers or any mixture thereof, or an acid addition saltthereof, wherein X is —O— or —S—, or —CR⁴R⁵—; and Y is—CR⁶R⁷—,—CR⁶R⁷—CR⁸R⁹—, or —CR⁶═CR⁷—; or X and Y together form a group—CR⁴═CR⁵—, or —CR⁴═CR⁵—CR⁶R⁷—; Z is —O— or —S—; A is selected from agroup of formula (II) and (IV)

wherein the dotted lines mean an optional bond; R¹, R², R³, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are each independently selected from hydrogen,halogen, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy,hydroxy, formyl, acyl, amino, alkylamino, dialkylamino, acylamino,alkoxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino,dialkylaminocarbonylamino, nitro and cyano; R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹are each independently selected from hydrogen and alkyl; and R¹¹ isselected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl,naphthyl, phenylalkyl, acyl and formyl.
 2. The compounds of claim 1wherein Z is —O—.
 3. The compounds of claim 1 wherein Z is —S—.
 4. Thecompounds of claim 1 wherein A is a group of formula (II).
 5. Thecompounds of claim 1 wherein A is a group of formula (IV).
 6. Thecompounds of claim 2 wherein A is a group of formula (II).
 7. Thecompounds of claim 2 wherein A is a group of formula (IV).
 8. Thecompounds of claim 3 wherein A is a group of formula (II).
 9. Thecompounds of claim 3 wherein A is a group of formula (IV).
 10. Thecompounds of claim 1 wherein R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are selected fromhydrogen or methyl.
 11. The compounds of claim 1 selected from the groupconsisting of6-Chloro-3-[2-[4-(2,2,5-trimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl]ethyl]-1H-indole;6-Chloro-3-[2-[4-(2,2,-dimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl]ethyl]-1H-indole;6-Chloro-3-[2-[4-(2,2,-dimethyl-2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydro-1-pyridy]ethyl]-1H-indole;3-[2-[4-(1,4-Benzodioxan-5-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-chloro-1H-indole;3-[2-[4-(1,4-Benzodioxan-5-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-fluoro-1H-indole;3-[2-[4-(1,4-Benzodioxan-5-yl)piperidin-1-yl]ethyl]-6-chloro-1H-indole;3-[2-[4-(1,4-Benzodioxan-5-yl)piperidin-1-yl]ethyl]-5-chloro-1H-indole;3-[2-[4-(1,4-Benzodioxan-5-yl)piperidin-1-yl]ethyl]-5-fluoro-1H-indole;6-Chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-1H-indole;3-[2-[4-(Benzofuran-7-yl-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-6-chloro-1H-indole;3-[2-[4-(Benzofuran-7-yl-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-bromo-1H-indole;3-[2-[4-(Benzofuran-7-yl-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-fluoro-1H-indole;3-[2-[4-(Benzofuran-7-yl)piperidin-1-yl]ethyl]-6-chloro-1H-indole;3-[2-[4-(Benzofuran-7-yl)piperidin-1-yl]ethyl]-5-fluoro-1H-indole;3-[2-[4-(1,4-Benzodioxan-5-yl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl]-6-chloro-1H-indole:3-[2-[4-(1,4-Benzodioxan-5-yl)-piperidin-1-yl]ethyl]-6-chloro-1H-indole;and 3-[2-[4-(Benzofuran-7-yl)piperidin-1-yl]ethyl]-5-bromo-1H-indole; oran acid addition salt thereof.
 12. A method of treating a disorder ordisease of a living animal body, said disorder or disease selected fromthe group consisting of an affective disorder, anxiety disorder, panicdisorder and obsessive compulsive disorder, comprising administering tosaid living animal body a therapeutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable acid addition salt thereof.13. An indole or 2,3-dihydro-indole derivative of the formula:

any of its enantiomers or any mixture thereof, or an acid addition saltthereof, wherein X is —O— or —S—, or —CR⁴R⁵—; and Y is —CR⁶R⁷—CR⁸R⁹—, or—CR⁶═CR⁷—; or X and Y together toxin a group —CR⁴═CR⁵—, or—R⁴═CR⁵—CR⁶R⁷—; Z is —O— or —S—; provided that when X and Z are both O,then Y is —CR⁶R⁷—CR⁸R⁹— or CR⁶═CR⁷—; A is selected from a group offormula (II), (III) and (IV)

wherein the dotted lines mean an optional bond; R¹, R², R³, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are each independently selected from hydrogen,halogen, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy,hydroxy, formyl, acyl, amino, alkylamino, dialkylamino, acylamino,alkoxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino,dialkylaminocarbonylamino, nitro and cyano; R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹are each independently selected from hydrogen and alkyl; and R¹¹ isselected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl,naphthyl, phenylalkyl, acyl and formyl.
 14. The compounds of claim 13wherein Z is —O—.
 15. The compounds of claim 13 wherein Z is —S—. 16.The compounds of claim 13 wherein A is a group of formula (II).
 17. Thecompounds of claim 13 wherein A is a group of formula (III).
 18. Thecompounds of claim 13 wherein A is a group of formula (IV).
 19. Thecompounds of claim 14 wherein A is a group of formula (II).
 20. Thecompounds of claim 14 wherein A is a group of formula (III).
 21. Thecompounds of claim 14 wherein A is a group of formula (IV).
 22. Thecompounds of claim 15 wherein A is a group of formula (II).
 23. Thecompounds of claim 15 wherein A is a group of formula (III).
 24. Thecompounds of claim 15 wherein A is a group of formula (IV).
 25. Thecompounds of claim 13 wherein R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are selectedfrom hydrogen or methyl.
 26. A method of treating a disorder or diseaseof a living animal body, said disorder or disease selected from thegroup consisting of an affective disorder, an anxiety disorder, panicdisorder and obsessive compulsive disorder, comprising administering tosaid living animal body a therapeutically effective amount of a compoundof claim 13, or a pharmaceutically acceptable acid addition saltthereof.